Integrated micro array system and methods therefor

ABSTRACT

Various methods are provided for an integrated micro array system ( 100 ) that allows fully automated sample processing and detection/quantification of nucleic acid and protein samples in a single analytical device, which may be configured to communicate data to a person other than the person operating the device. The integrated micro array system has a housing ( 110 ) in which robotics assembly ( 120 ) controls motion of automatic pipette ( 124 ) and second actuator ( 122 ) that control motion of the automatic actuator ( 123 ). Fluidics station ( 130 ) includes a plurality of multi-reagent packs ( 132 ). Sample station ( 140 ) comprises a plurality of sample vessels ( 142 ). Pipette tip storage area ( 150 ) and magazine holder ( 160 ) that includes a plurality of magazine ( 162 ). The system also comprise of a sample processing platform ( 170 ), a stringency station ( 181 ), and optical detector ( 180 ), and a data transfer device ( 190 ).

FIELD OF THE INVENTION

The field of the invention is micro array systems, and particularlyautomated micro array systems.

BACKGROUND OF THE INVENTION

Recent advances in genomics and proteomics research made numerousnucleotide and peptide sequences available, necessitatinghigh-throughput screening of samples for presence and/or quantity ofgenes and/or gene expression. While automation of individual steps(e.g., DNA isolation, protein fractionation, etc.) in high-throughputscreening may be performed using relatively simple instrumentconfigurations, integration of multiple and distinct steps in automatedhigh-throughput screening remains problematic.

For example, sample analysis for detection and quantification of one ormore analytes may be performed in nano-volumes on a single chip (seee.g., “Lab-on-a-chip” from Agilent or Caliper Technologies). Suchmultiple analyte detection can advantageously be performed in relativelyshort time using minimal amounts of sample. Moreover, all steps fromhandling of the sample after application of the sample to detection andanalysis are performed within the same device. However, identificationand quantification of the detected analyte using nanoelectrophoresis istypically restricted to the size of the analyte. Moreover, resolution ofindividual analytes becomes increasingly difficult as the size or chargedifference between the analytes decreases. Consequently, suchnanoelectrophoretic systems are generally limited to characterization ofan analyte by its molecular weight.

Where high resolution of molecular weights of an analyte is particularlyimportant, analysis of complex samples may be coupled with laserdesorption—time of flight mass spectroscopic analysis (see e.g.,Ciphergen Biosystems' LD-TOF multi-analyte desorption chips, orSequenome chip). Here, components of a complex sample are immobilized ona carrier chip (e.g., chip with anion exchange resin or hydrophobicinteraction resin) and subjected to size analysis after desorptionaccording to their molecular properties in an analysis system. LD-TOFcoupled analysis is typically highly sensitive and often requires onlyminimal sample preparation. Moreover, LD-TOF coupled analysis providesrelatively high resolution among particular analytes. However,identification of particular analytes is still mostly limited to sizedetermination.

Alternatively, and especially where the analyte is a DNA or RNA, variousformats of automated modular PCR-based analysis are known in the art.For example, where a single sample is analyzed for presence or absenceof a particular sequence, all or almost all of the reagents and samplemay be introduced into an automated system from a single cartridge (seee.g., Cepheid's i-CORE system). On the other band, and especially wherea relatively high number of samples are concurrently analyzed, a fullrobotic PCR station may be employed (see e.g., Orchid Biocomputer SNPAnalysis system). Such systems typically provide an analysis procedurethat integrates sample manipulation with nucleic acid amplification andproduct analysis. However, automated modular PCR-based analysistypically rely on amplification of target DNA to generate appreciablesignals, thereby introducing significant complexity and numerouserror-prone procedures. Moreover, while PCR based systems are frequentlyoperated in a dedicated environment using dedicated equipment to preventnon-sample specific signals, problems associated with contamination viasample carry-over may still persist. Thus, automated modular PCR-basedanalysis tends to be highly expensive, and is generally limited toexclusive analysis of nucleic acids.

In still further examples, nucleic acid-containing samples can beanalyzed by their hybridization characteristics with at least partiallycomplementary and immobilized nucleic acids, thereby providingquantitative and qualitative information on a particular sample.Hybridization of a nucleic acid to corresponding solid-phase immobilizednucleic acids may be controlled by variation of temperature and/or ionicstrength of the environment of the nucleic acid hybrid, and there arenumerous systems known in the art.

For example, high density arrays of immobilized oligonucleotides on asilicon chip may be exposed to a sample containing nucleic acids thatare complementary to at least some of the immobilized oligonucleotides(see e.g., Affymetrix' GeneChip system). In such systems, a processedsample (typically a labeled and biotinylated in-vitro transcript of apreviously prepared cDNA) is provided to the chip in a fluidics stationthat further controls flow of reagents and hybridization temperature.After complementary labeled nucleic acids have hybridized to thecorresponding nucleic acids on the chip, the chip is removed from thefluidics station and manually transferred to a scanner station in whichthe sample is analyzed via detection of the fluorescent labels. Whilesuch analytic devices typically allow a user to determine identity,presence, and/or quantity of a vast number of DNA/RNA analytes in asample, substantial sample preparation (typically several hours to morethan one day) and hybridization times (e.g., about 16 hours at 40° C.)are frequently necessary. Moreover, analytes detected and quantifiedusing such systems tend to be limited to nucleic acids.

Alternatively, sample capture and hybridization may be controlled viaelectrostatic forces (see e.g., Nanogen's NanoChip system). In suchsystems, capture probes and hybridization conditions may be individuallycontrolled, thereby allowing custom addressing of individual analytepixels. However, due to the complexity of loading and readingprocedures, the analytic process is split among at least two independentdevices: Analytes are typically bound in a loader section, while areader (ie., array processor and scanner) will perform the readout ofthe sample.

In another system, detection may be performed using an electronic chipthat provides a signal upon binding of a signaling oligonucleotide to ananalyte oligonucleotide that is bound to a corresponding oligonucleotidethat is immobilized on the chip (see e.g., Motorola's iSensor system).While electronic detection and quantification may provide at least someadvantages, most of such systems are prone to non-specificfalse-positive and/or false-negative signals due to contamination.Moreover, analytes detected and quantified using such systems tend to belimited to nucleic acids.

Thus, although various systems for micro array systems are known in theart, numerous problems still remain. Among other things, while varioussystems may provide at least some automation, fluid handling and sampledetection/quantification of analyte binding are typically operated inseparate devices, thus requiring at least some user intervention afterthe sample is applied to the system. Furthermore, all or almost all ofthe known micro array systems are limited to analysis of either nucleicacids or peptides. Therefore, there is still a need for an improvedmethods and systems for automated analytic devices.

SUMMARY OF THE INVENTION

The present invention is directed to methods of operating analyticaldevices, and especially to methods of operating automated micro arraysystems that allow fully automated sample processing anddetection/quantification of various analytes (e.g., nucleic acid,protein samples, low molecular weight compounds, etc.) in a singleanalytical device.

In one aspect of the inventive subject matter, a method of analyzing ananalyte on a biochip has one step in which an analytical device isprovided that includes a first section and a second section that receivea biochip having a plurality of substrates in a plurality ofpredetermined positions. In another step, the biochip is contacted inthe first section with a sample containing a non-analyte and an analyteunder conditions that allow binding of the analyte to at least one ofthe substrates, and in a still another step, the first section isoperationally to the second section such that the biochip isautomatically transferred from the first section to the second section.In a further step, binding of the analyte to the at least one of thesubstrates on the biochip is optically detected in the second section.

Contemplated biochips may be provided to the first section from amagazine using an automatic actuator, wherein the magazine is disposedwithin the analytical device, and it is further preferred that the firstsection may be configured to receive at least a second biochip. Thefirst section may additionally include an energy source (e.g.,ultrasound, microwave, and/or heat/cool source). Contemplated samplesmay include biological fluids with tissue, nucleic acids, peptides,and/or enzyme inhibitor as analytes. Consequently, suitable substratesinclude nucleic acids, peptides, and/or enzymes, which may or may not benon-covalently coupled to the biochip via a crosslinker.

Preferred steps of contacting may include pipetting the sample with anautomatic pipette that is disposed within the analytical device, whereinthe biochip may or may not be heated. Especially contemplated steps ofoperationally coupling include providing an automatic actuator thatmoves the biochip from a first platform of the first section to a secondplatform of a second section, while preferred steps of opticallydetecting include detection of a fluorescence signal, achemiluminescence signal, and/or a phosphorescence signal with aconfocal microscope or a dark field microscope, which may be focusedusing a reference signal from a reference marker that is disposed on thebiochip.

In another aspect of the inventive subject matter, a method of analyzingan analyte on a biochip may include one step in which a biochip with areference marker and a plurality of substrates is provided, wherein atleast one of the substrates binds an analyte. In another step, thereference marker (e.g., comprising a fluorophor, luminogenic substrate,and/or a phosphorescent compound) is illuminated to create a referencesignal, and the analyte is illuminated to create an analyte signal. Inyet another step, a focal plane is determined for an optical detectorusing the reference signal and adjusting the optical detector to thefocal plane, and in a further step, the analyte signal is acquired usingthe optical detector.

Preferred illumination of the reference marker and/or the analyteincludes dark filed illumination, and illumination of the analyte with alaser is particularly preferred. Further especially contemplatedilluminations for the reference marker and the analyte may be performedusing independent light sources.

In a further aspect of the inventive subject matter, a method ofoperating an analytical includes one step in which an analytical deviceis provided comprising a data transfer interface coupled to a detector,a multi-reagent pack, an automatic pipette, and/or a sample processingplatform. In another step, the data transfer interface is electronicallycoupled with a person other than a user of the analytical device, and instill another step, data are provided from the detector, themulti-reagent pack, the automatic pipette, and/or the sample processingplatform to the person via the data transfer interface. In a furtherstep, the data are employed to analyze operational status of theanalytical device.

Particularly preferred methods of operation include those in which theperson other than the user is in a remote location relative to theanalytical device, and in which the step of providing is executed via anInternet or via a modem connection. Data may be provided in response toan action of the user of the analytical device, or in response to arequest by the person other than the user. Contemplated data may relateto the batch number, date manufactured, expiration date, or type ofreagent in the multi-reagent pack, volume of the reagent in themulti-reagent pack, volume of liquid transferred using the automaticpipette, temperature of the sample processing platform, type of testperformed using the analytical device. Consequently, operational statusof the analytical device may include inoperability of one or morecomponents and/or lack of one or more reagents.

In yet another aspect of the inventive subject matter, a method ofmarketing includes one step in which an analytical device is providedcomprising a data transfer interface that receives status data of acomponent in the analytical device. In another step, the data transferinterface is electronically coupled with a system in a remote locationrelative to the analytical device, and in yet another step, status dataare provided to the remote system using the data transfer interface. Ina still further step, the status data are used in the remote system toinitiate delivery of a replacement for the component.

Especially contemplated analytical devices analyze binding of an analyteto a substrate on a biochip, and particularly contemplated componentsinclude reagents, wherein the status data of the component is the volumeof the reagent in the analytical device. Electronic coupling may beperformed via modem or other data transfer connection to the Internet,and delivery of the status data may be controlled by a predeterminedschedule executed on a processor of the analytical device or by apredetermined schedule executed on a processor of the system in theremote location. Especially preferred initiation of delivery includesautomatic generation of a purchase order or inventory control (e.g.,packaging and/or labeling of the component, or alert to the customer toindicate status/low supply of the component).

Various objects, features, aspects and advantages of the presentinvention will become more apparent from the following detaileddescription of preferred embodiments of the invention, along with theaccompanying drawings in which like numerals represent like components.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1A is a schematic view of an exemplary analytical device accordingto the inventive subject matter.

FIG. 1B is a perspective view of an exemplary analytical deviceaccording to the inventive subject matter.

FIG. 2 is a flow chart of a method of analyzing an analyte on a biochipaccording to the inventive subject matter.

FIG. 3 is a flow chart of another method of analyzing an analyte on abiochip according to the inventive subject matter.

FIG. 4 is a flow chart of a method of operating an analytical deviceaccording to the inventive subject matter.

FIG. 5 is a flow chart of a method of marketing according to theinventive subject matter.

DETAILED DESCRIPTION

The inventors discovered that one or more analytes can be detectedand/or quantified using an integrated analytical device that employs abiochip, wherein (a) processing of the analyte and/or biochip, detectionand/or quantification of the analyte is integrated into a process thatdoes not require user intervention, and (b) the integrated analyticaldevice is configured to allow concurrent or subsequent analysis ofvarious biochemically diverse analytes, including nucleic acids,peptides, and small molecules (e.g., enzyme substrates or inhibitors,etc.).

As used herein, the term “analytical device” refers to any device orcombination of devices that is employed to detect and/or quantify one ormore analytes. Particularly preferred analytical devices include microarray systems, wherein the term “micro array system” refers to anintegrated system in which a plurality of analytes are bound to aplurality of substrates on a biochip in predetermined positions, and inwhich presence and/or quantity of at least one of the analytes isdetermined.

As also used herein, the term “biochip” generally refers to a carrierupon which a plurality of substrates are immobilized in predeterminedpositions, and wherein at least one of the substrates binds an analytefrom a sample. One class of particularly preferred biochips includes acarrier coupled to a multi-functional matrix layer that is coupled to asubstrate, wherein the multi-functional matrix layer provides reductionof at least one of an autofluorescence of the carrier, anincident-light-absorption of the carrier, a charge-effect of thecarrier, and a surface unevenness of the carrier, and wherein thesubstrate binds to an analyte that is disposed in a sample fluid whenthe sample fluid contacts the biochip.

Alternatively, another class of especially contemplated biochipscomprises a plurality of first substrates in a plurality of firstpredetermined positions, wherein each of the plurality of firstsubstrates belongs to a class selected from the group consisting of apolypeptide, a polynucleotide, a carbohydrate, and a pharmacologicallyactive molecule. A plurality of second substrates in a plurality ofsecond predetermined positions may further be included in such biochips,wherein each of the plurality of second substrates belongs to a classselected from the group consisting of a polypeptide, a polynucleotide, acarbohydrate, and a pharmacologically active molecule, and wherein theclass of each of the first substrates and the class of each of thesecond substrates is not the same. Particularly contemplated biochipsare described in co-pending U.S. patent application with the Ser. No.09/735,402 (filed Dec. 12, 2000) and copending PCT application with theserial number PCT/US01/47991 (filed Dec. 11, 2001), both of which areincorporated by reference herein.

Contemplated biochips may further be disposed in a housing (which may ormay not be closed), and particularly preferred biochips comprise ahousing at least partially enclosing a multi-substrate chip thatincludes a reference marker and a plurality of substrates inpredetermined positions, wherein the reference marker is illuminated bya first light source at a first angle, and wherein at least one of theplurality of substrates is illuminated by a second light source at asecond angle, and wherein the housing is configured such that the firstangle and the second angle are not identical. Further particularlycontemplated biochips are described in co-pending PCT application withthe serial number PCT/US02/03917 (filed Jan. 24, 2002), which isincorporated by reference herein.

As further used herein, the term “analyte” refers to a molecule orassembly of molecules whose presence, quantity, or activity is to bedetermined from a sample. Particularly contemplated analytes includenatural and synthetic nucleic acids, natural and synthetic peptides,pharmacologically active molecules, biological effectors, viruses andportions thereof, bacterial cells and portions thereof, and eukaryoticcells and portions thereof.

For example, where the analyte comprises a natural or synthetic nucleicacid, suitable analytes include oligo- and polynucleotides, DNA and RNA(e.g. cDNA, amplified DNA, in-vitro transcripts, tRNA, rRNA, etc.),nucleic acid analogs (e.g. peptide nucleic acids, phosphorothioatenucleic acids, etc.) and covalent and non-covalent complexes of nucleicacid with functional or non-functional moieties (e.g., radioisotopes,biotin, fluorophor, etc.). Similarly, where the analyte comprises anatural or synthetic peptide, suitable peptides include oligopeptides(e.g., 2-20 amino acids), polypeptides (e.g., 21-20000 amino acids, andhigher), linear, cyclic, and/or branched peptides that may includenatural and/or non-natural amino acids (in D- or L-configuration), andcovalent and non-covalent complexes of peptides with functional ornon-functional moieties (e.g. glycoproteins, lipoproteins, biotin,radioisotope labels, etc.).

Contemplated pharmacologically active molecules includes those thatinteract with reproduction, structural integrity, and/or metabolism of acell. Consequently, suitable molecules include those interacting withvarious biological processes including apoptosis, mitosis or meiosis,tubulin assembly and disassembly, enzyme inhibitors or activators, andcis-and trans acting regulatory elements for DNA/RNA expression.Biological effectors particularly include secreted effectors for variousorgan and systemic functions and include hormones, cytokines,chemokines, and antibodies. With respect to viruses, bacterial andeukaryotic cells it should be recognized that all known viruses, one ormore bacterial and eukaryotic cells and fragments thereof (e.g.,membranes and their components, ribosomes and their components, variousorganelles and their components, etc.) are contemplated suitable for useherein. Further contemplated analytes may also include tissue, andespecially animal tissue.

In a further especially contemplated aspects, analytes may also becharacterized in their ability to (specifically) bind to one or moresubstrates, wherein the term “binding of the analyte” refers of anon-covalent interaction between the analyte and a substrate to form acomplex having a dissociation constant K_(D) of equal or less than 10⁻⁴Mat physiological pH, 20° C., and total salt concentration of less than150 mM. It should further be appreciated that the term “binding of theanalyte” specifically includes binding of a substrate to an enzyme atthe active site of the enzyme. Consequently, the term “substrate” asused herein refers to any composition, molecule or assembly of moleculesthat can bind an analyte to form a complex having a dissociationconstant K_(D) of equal or less than 10⁴M at physiological pH, 20° C.,and total salt concentration of less than 150 mM. Particularly preferredsubstrates include natural and synthetic nucleic acids (e.g.,oligonucleotides), natural and synthetic peptides and especiallyantibodies (and fragments thereof), enzymes, small molecules, viruses orfragments thereof, and one or more bacterial and eukaryotic cells andfragments thereof (e.g., membranes and their components, ribosomes andtheir components, various organelles and their components, etc.) arecontemplated suitable for use herein. Further contemplated substratesmay also include tissue, and especially animal tissue.

Thus, the term “non-analyte” refers to any composition, molecule, orassembly of molecules that is not an analyte either by virtue of lack ofspecific binding and/or by virtue of the chemical composition. Forexample, where a sample comprises a cytokine and a ribosomal protein,and wherein the substrate comprises an antibody directed against thecytokine, the cytoline will act as the analyte and the ribosomal proteinwill act as the non-analyte. However, it should be recognized that asample may also comprise molecules that bind to a substrate withrelatively high affinity wherein only one of the molecules is an analyteand the other molecules is not analyte (e.g., single stranded nucleicacid with single base pair mismatch in complementarity relative to asubstrate and a single stranded nucleic acid with perfectcomplementarity relative to the substrate). Here, depending on the testconditions, the analyte may be only one of the analytes or both of theanalytes.

FIG. 1A schematically depicts an exemplary integrated micro array system100 having a housing 110 in which a robotics assembly 120 controlsmotion of automatic pipette 124 and secondary actuator 122 that controlsmotion of automatic actuator 123. Fluidics station 130 includes aplurality of multi-reagent packs 132. Sample station 140 preferablycomprises a plurality of sample vessels 142 (e.g., a microplate withmicrowells). Pipette tip storage area 150 includes disposable pipettetips for the automatic pipette 124, and magazine holder 160 includes aplurality of magazines 162 that store at least two, and more typicallyat least eight biochips. The biochips are moved from the magazine to 162to a sample processing platform 170 (which may further include an energysource such as an ultrasound source, a microwave source, a heater,and/or a cooler), where the biochip may receive the sample pipetted fromthe sample vessel 142. Alternatively, a stringency station 181 may beincluded to achieve higher hybridization specificity (e.g., a thermoelement that provides heat and/or cooling to the biochip when positionon the stringency station). Subsequent steps of incubation, heating,cooling, adjusting of stringency, and/or washing are then performed onthe biochip while the biochip is on the sample processing platform topromote binding of the analyte to the substrate, and to removenon-analytes from the platform. Reagents needed for such samplemanipulation steps (including staining reagents for bound analytes) areadvantageously retrieved from multi-reagent packs 132. Once the analyteis properly processed on the biochip, the biochip is moved from theplatform to the optical detector 180 via automatic actuator 123 fordetection and/or quantification of the analyte. A data transfer device190 is electronically coupled to various components of the analyticaldevice and provides data to a remote system or person other than theoperator (not shown). A perspective view of an exemplary analyticaldevice is depicted in FIG. 1B.

Thus, in one particularly preferred aspect of the inventive subjectmatter, a method of analyzing an analyte on a biochip will include astep in which an analytical device is provided that has a first sectionand a second section, and wherein both sections receive a biochip havinga plurality of substrates in a plurality of predetermined positions. Inanother step, the biochip is contacted in the first section with asample containing a non-analyte and an analyte under conditions thatallow binding of the analyte to at least one of the substrates. In yetanother step, the first section is operationally coupled to the secondsection such that the biochip is automatically transferred from thefirst section to the second section, and in still another step, bindingof the analyte to the at least one of the substrates on the biochip isoptically detected in the second section.

Particularly contemplated analytical devices include those in whichdetection and at least one of (a) sample application to the biochip, (b)binding of an analyte to a substrate on the biochip, (c) adjusting thehybridization stringency (e.g. via change in temperature of the analytesubstrate complex, or change in ionic strength in the environment of theanalyte substrate complex, or change in solvent), and (d) washing thebiochip such that the analyte remains bound and at least 75% (moretypically at least 95%, and most typically at least 99%) of thenon-analyte is washed off the biochip are performed within the samedevice, preferably without user intervention (i.e., without a usermanually manipulating the biochip). Further especially contemplatedanalytical devices include integrated micro array systems that mayfurther comprise at least one of a sample processing platform, one ormore multi-reagent packs, a robotics assembly, and an optical or otherdetector.

With respect to the first section it is contemplated that such sectionsmay have various configurations so long as such first sections areconfigured to receive a biochip, wherein the biochip can be contactedwith a sample containing a non-analyte and an analyte under conditionsthat allow binding of the analyte to at least one of the substrates onthe biochip. Consequently, particularly suitable first sections willinclude a generally flat surface that engages with the biochip, or mayinclude at least one guide element (e.g., a rail, a protrusion, or otherelement) that engages with the biochip to receive and retain the biochipin a predetermined position. For example, appropriate first sections maybe shaped in form of a generally flat platform, a U-shaped tray thatreceives the biochip. Furthermore, it should be appreciated thatcontemplated first sections may be configured such that they receive atleast a second biochip, and in especially preferred aspects, suitablefirst sections will be configured to receive typically between one and10 biochips.

Particularly preferred first sections may be configured to providepreselected conditions that allow binding of the analyte to at least oneof the substrates. For example, suitable first sections may be coupledto an energy source that provides energy to the biochip (and thus to thesubstrate-analyte complex) directly or indirectly. Where direct energytransfer is desired, the energy source may include thermalradiation/convection and/or electromagnetic radiation (e.g., a microwavesource) to deliver the energy to the substrate-analyte complex on thebiochip. Alternatively, direct energy sources may also includeultrasound probes that contact a fluid in the biochip, wherein the fluidincludes the substrate-analyte complex.

On the other hand, where indirect energy transfer is desired, suitableenergy sources include thermal elements (e.g., Peltier element, heater,or cooler) or other heater and/or cooler elements that provide heat orcooling to the substrate-analyte complex on the biochip through thefirst section. For example, suitable first sections may be fabricatedfrom aluminum and may include a Peltier element coupled on one side,while the biochip will be disposed on the opposite side.

In still further especially preferred aspects, the biochip is providedto the first section from a magazine using an automatic actuator thatmoves the biochip from the magazine along at least one coordinate to thefirst section (the magazine is preferably disposed within the analyticaldevice). For example, a magazine may be positioned proximal to the firstsection and include two openings, wherein the actuator is directed intothe first opening and the biochip proceeds through the second openingonto the first section (e.g. sample processing platform). However, inalternative aspects, the biochip may also be provided to the firstsection manually by the user or automatically via any appropriatefeeding mechanism. For example, contemplated feeding mechanisms includechutes, conveyor belts, etc. Moreover, it should be recognized that thefirst section may be moved relative to the second section (or othercomponent in the analytical device), and it is especially preferred thatthe first section is movable along at least one coordinate in theanalytical device (e.g., on a rail moved by a stepper motor)

With respect to the second section, it is generally preferred that thesecond section will receive the biochip (preferably directly from thefirst section) and further comprises an optical detector that detectsbinding of the analyte to the substrate on the biochip. Thus, suitablesecond sections will be located within the analytical device in aposition proximal to the first section and are preferably configuredsuch that the biochip can be directly and automatically moved from thefirst to the second section (e.g. include a generally horizontalsurface, guide rail or other element that engages with the biochip toreceive and retain the biochip).

For example, direct and automatic movement (i.e., movement without theuser manually moving the biochip) of the biochip may includehorizontally moving the biochip from an adjacent first platform to thesecond platform using an automatic actuator or a conveyor belt-typemechanism. On the other hand, direct and automatic movement of thebiochip may also include sliding the biochip from a level that is higherthan the second section to the second section (e.g., by tilting thefirst section). Alternatively, movement of the biochip may also includedirect and automatic transfer of the biochip from the first section tothe second section using a robotic assembly that controls movement ofthe biochip along two, and more typically three coordinates.

Furthermore, it is contemplated that suitable second sections may be ina fixed or movable position within the analytical device, and where thesecond section is movable, it is contemplated that movement of thesecond section may be along one, two, or three coordinates. Moreover, itis contemplated that in preferred aspects of integrated micro arraysystems at least one environmental parameter in the second section maybe controlled. For example, in particularly contemplated configurationsof second sections, temperature and humidity may be controlled (e.g.,via Peltier element and/or humidifier).

Contemplated optical detectors generally include all optical devicesthat can detect an optical signal in a predetermined position on thebiochip, and especially contemplated detectors include a photomultipliertube, a charge coupled device (CCD), which may be optically coupled to aconfocal, and/or dark field microscope. Contemplated optical signalsdetected by such optical detectors include a fluorescence signal, achemiluminescence signal, and/or a phosphorescence signal. There arenumerous optical detectors known in the art to detect optical signalsfrom biochips, and all of the known devices are considered suitable foruse herein. In further preferred configurations, the biochip includes areference marker that produces a reference signal upon illumination, andthe optical detector is focused using a reference signal (infra).

Therefore, depending on the particular configuration of first and secondsections, it should be appreciated that there are numerousconfigurations of operational coupling the first section to the secondsection. However, it is generally contemplated that all modes ofoperational coupling will allow automatic transfer of the biochip fromthe first to the second section. The term “automatic transfer” of thebiochip as used herein means that the biochip is moved from the first tothe second section without a user manually contacting and/or moving thebiochip. Consequently, operational coupling may be achieved bypositioning the first and second sections relative to each other suchthat a biochip may be automatically transferred (e.g., via roboticassembly, conveyor belt, or actuator that moves in one or moredirections) from the first to the second section, wherein contemplatedpositioning may include a fixed position of one section relative to theother section (e.g., first and second sections are in a fixed andabutting position), or a movable positioning where one section movesrelative to the other section (e.g., first section moves along a guiderail actuated by a motor into abutting position with the secondsection).

Suitable analytical devices may further include various sensors thatprovide a computer (electronically coupled to the analytical device andcontrolling at least some of the functions [e.g., length and temperatureof incubation steps, type of assay performed, data analysis, etc.] ofthe analytic device) with environmental information, and especiallypreferred sensors include a humidity sensor and/or a temperature sensor.Yet further contemplated sensors may include barcode readers, and it isespecially preferred that the barcode reader(s) will read barcodes on atleast one of the reagent pack, the biochip, and the sample container.

With respect to contemplated biochips, it is generally contemplated thatsuitable biochips will include a carrier to which a plurality ofsubstrates in predetermined positions are coupled, wherein at least oneof the substrates is capable of selectively binding an analyte. Oneclass of particularly preferred biochips includes a carrier coupled to amulti-functional matrix layer that is coupled to a substrate, whereinthe multi-functional matrix layer provides reduction of at least one ofan autofluorescence of the carrier, an incident-light-absorption of thecarrier, a charge-effect of the carrier, and a surface unevenness of thecarrier, and wherein the substrate binds to an analyte that is disposedin a sample fluid when the sample fluid contacts the biochip.

Alternatively, another class of especially contemplated biochipscomprises a plurality of first substrates in a plurality of firstpredetermined positions, wherein each of the plurality of firstsubstrates belongs to a class selected from the group consisting of apolypeptide, a polynucleotide, a carbohydrate, and a pharmacologicallyactive molecule. A plurality of second substrates in a plurality ofsecond predetermined positions may further be included in such biochips,wherein each of the plurality of second substrates belongs to a classselected from the group consisting of a polypeptide, a polynucleotide, acarbohydrate, and a pharmacologically active molecule, and wherein theclass of each of the first substrates and the class of each of thesecond substrates is not the same. In especially contemplated aspects,at least one of the plurality of substrates is non-covalently coupled tothe biochip via a crosslinker. Particularly contemplated biochips aredescribed in co-pending U.S. patent application with the Ser. No.09/735,402 and copending PCT application with the serial numberPCT/US02/47991 (supra).

Contemplated biochips may further be disposed in a housing (which may ormay not be closed), and particularly preferred biochips comprise ahousing at least partially enclosing a multi-substrate chip thatincludes a reference marker and a plurality of substrates inpredetermined positions, wherein the reference marker is illuminated bya first light source at a first angle, and wherein at least one of theplurality of substrates is illuminated by a second light source at asecond angle, and wherein the housing is configured such that the firstangle and the second angle are not identical. Further particularlycontemplated biochips are described in co-pending PCT application withthe serial number PCT/US02/03917 (supra).

In especially preferred aspects of contemplated methods, a secondbiochip with a plurality of second substrates in a plurality ofpredetermined positions may be provided to at least one of the first andsecond sections, and the second biochip is contacted in the firstsection with a sample containing a second non-analyte and a secondanalyte under conditions that allow binding of the second analyte to atleast one of the second substrates of the second biochip. While notlimiting to the inventive subject matter, it is contemplated that thesubstrates of the first biochip and the second biochip belong todifferent classes. For example, while the first biochip may includenucleic acids as substrates, the second biochip may include peptides asa substrate. Of course, it should also be recognized that contemplatedbiochips may also include at least two different types of substrates,wherein contemplated types of substrates include nucleic acids,peptides, small molecules, pharmaceutically active molecules, a virus,bacterial or eukaryotic cell or fragments thereof, and tissues.Consequently, particularly preferred samples include biological fluids(e.g., whole or processed blood, plasma, serum, biopsy specimens, urine,spinal fluid, saliva, etc.), wherein particularly preferred analytesinclude tissues, nucleic acids, peptides, and enzyme inhibitors.

Depending on the particular type of sample and/or substrate on thebiochip, it is generally contemplated that the step of contacting thebiochip with the sample includes an automatic application, however,manual application of the sample to the biochip is also consideredsuitable. In a particularly preferred aspect, the sample is a liquid andis pipetted with an automatic pipette (i.e., aspiration of the fluid isperformed using a motor or electric vacuum pump) that is disposed withinthe analytical device. There are numerous automatic pipettes known inthe art and all of the known automatic pipettes are considered suitablefor use herein. Especially preferred automatic pipettes are Gilson,Eppendorf, and Rainin automatic pipettors, which may or may not befurther modified.

Particularly preferred modifications of contemplated automatic pipetteswill include at least one of a volume sensor and a tip height sensor.For example, one particularly preferred volume sensor may employ a laserbeam within the pipette tip, wherein the laser beam is employed todetermine the height (and with this the volume) of the aspirated liquidwithin the tip. Another especially preferred aspect includes anultrasound (or second laser) beam that is employed to determine thedistance between the fluid dispensing end of the pipette tip and asurface to which the fluid is to be dispensed.

With respect to the step optically detecting binding of the analyte, itis generally contemplated that all known detection methods are suitablefor use herein. However, in particularly preferred detection steps,non-analytes are removed from the biochip prior to detection byproviding conditions that promote dissociation or non-binding of thenon-analyte. For example, suitable conditions may include washing withwash fluids (e.g., provided by a multi-reagent pack), a temperaturechange (e.g., heating), sonication, etc. Optical detection of bindingmay be performed using detection of radiation, luminescence, or lightabsorption of a dye or other marker that is coupled to the analyte(wherein the step of coupling the dye or other marker may be performedin a separate step).

Particularly preferred detections include detection ofchemiluminescence, fluorescence, and/or phosphorescence, which may beperformed using a photomultiplier in conjunction with a dark fieldmicroscope or confocal microscope (which may be located in a separatesection or the section). Especially preferred optical detection includesa step in which the focal plane is determined in a process that avoidsillumination (and therefore photo-bleaching) of the analyte that isbound to the substrate.

Thus, in another especially preferred aspect of the inventive subjectmatter, a method of analyzing an analyte on a biochip may includeproviding a biochip with a reference marker and a plurality ofsubstrates, wherein at least one of the substrates binds an analyte,illuminating the reference marker to create a reference signal, andilluminating the analyte to create an analyte signal, determining afocal plane for an optical detector using the reference signal andadjusting the optical detector to the focal plane, and acquiring theanalyte signal using the optical detector.

With respect to the biochip, the same considerations as discussed aboveapply. Particularly contemplated biochips will include at least one,more preferably two, and most preferably four reference markers (whichmay be positioned at the corners of the biochip), wherein suitablereference markers include numerous optically detectable elements. Amongother elements, suitable reference markers include fluorophors,luminogenic substrates, and phosphorescent compounds. Alternatively, dyeof dye mixtures may also be suitable.

Furthermore, appropriate biochips may have one or more classes ofsubstrates (which may or may not be chemically distinct), andcontemplated substrates include nucleic acids, peptides, and enzymeinhibitors, wherein at least one of the substrates is non-covalentlycoupled to the biochip via a crosslinker. Especially preferredcrosslinkers include known affinity pairs, which may comprise peptidesor small molecules. For example, contemplated crosslinkers arebiotin/streptavidin, antibody (fragment)/hapten, chelatednickel/polyHistidyl moiety, etc., wherein either of the affinity pairmay be (covalently or non-covalently) coupled to the biochip.Consequently, binding of the analyte to the substrate is preferablynon-covalent binding, however, covalent binding is not excluded.

In further preferred aspects, the biochip is moved within the analyticaldevice from a sample processing platform (e.g., the first section,supra) to a detector (e.g., in the second section, supra) using anautomatic actuator. Contemplated automatic actuators include roboticactuators that are controlled in at least two, and more preferably threedimensions via step motors. However, other means of moving are alsocontemplated suitable and include conveyor belts, slides, etc.

Contemplated steps of illuminating the reference marker may be performedin numerous manners so long as the reference marker receives sufficientlight to enable optical detection and focusing. Thus, suitableillumination of the reference marker includes dark field illumination(e.g., through the housing of the biochip), which is particularlypreferably where the analyte comprises a light-sensitive marker.However, direct illumination of the reference marker is alsocontemplated suitable for use herein. Consequently, the light sourcesfor illumination may vary considerably and may include illumination ofthe reference marker with a light source other than the light sourceemployed for illumination of the analyte. Exemplary light sourcesinclude various laser and laser diodes, LED diodes, incandescent andfluorescent light sources, etc.

Therefore, the reference marker may be employed to determine the focalplane of the detection device (preferably confocal microscope) byilluminating the reference marker which is in known spatial relationshipto the position of the analyte. Consequently, and especially where morethan one reference marker is employed, correct focusing of analytesdisposed on an uneven surface of the biochip is possible without anotherwise required step of refocusing to each new analyte. Furthermore,the use of an independent reference marker will advantageously allowillumination of the biochip (for focusing purposes) with light at awavelength that will provide significantly reduced photo-damage to theanalyte, or even no photo-damage at all. Adjustment of the opticaldetector may be performed in various manners and will typically includea relative movement between the optical detector and the biochip in atleast one dimension. However, it is generally preferred that the biochipis moved within the detection unit on a platform that can be moved in atleast one dimension, and more typically on a platform that can be movedin all three dimensions.

Thus, the analyte signal (which may be directly generated by the analyteor indirectly by a marker coupled to the analyte) includes signalsselected from the group consisting of a fluorescence signal, achemiluminescence signal, and a phosphorescence signal. The particularnature of the signal will typically be determined at least in part bythe particular analyte, and a person of ordinary skill in the art willreadily determine the appropriate signal source.

In a still further especially contemplated aspect of the inventivesubject matter, and particularly where the analytical device includes adata transfer interface, the inventors contemplate a method of operatingan analytical device that includes a step of providing an analyticaldevice comprising a data transfer interface coupled to at least one of adetector, a multi-reagent pack, an automatic pipette, and a sampleprocessing platform, electronically coupling the data transfer interfacewith a person other than a user of the analytical device, providing datafrom at least one of the detector, the multi-reagent pack, the automaticpipette, and the sample processing platform to the person via the datatransfer interface, and using the data to analyze operational status ofthe analytical device.

Especially suitable data transfer interfaces include electronic datatransfer interfaces used in personal computers such as telephone orcable modems. Consequently, suitable data transfer interfaces arepreferably controlled by a microprocessor (most preferably themicroprocessor that controls operation of the analytic device) withinthe analytical device. In a particularly contemplated mode of operation,the data transfer interface is temporarily electronically connected to aremote computer via a telephone modem, wherein either the analyticaldevice or the remote compute initiates electronic communication.

In particularly contemplated aspects, the data transfer interface iselectronically coupled to the detector, a multi-reagent pack, theautomatic pipette, and/or the sample processing platform, wherein thedata transfer interface receives or provides data from the detector,multi-reagent pack, automatic pipette, and/or sample processingplatform. For example, the detector may provide data relating to signalstrength, wavelength, calibration signals, or type of assay to theinterface, while the multi-reagent pack may provide data regarding the(remaining) contents of the reagents in the pack, the type of testperformed, the date the pack was purchased and/or first used, etc.Similarly, the automatic pipette may provide data relating to number ofpipetting functions, size of tips employed, etc. Thus, the data transferinterface may collect and/or disseminate data that are relevant for theoperational status of the analytical device. Consequently, it should beappreciated that the data transfer interface is a bi-directional datatransfer interface, that is, data are provided to and from theanalytical device.

Consequently, in one aspect of the inventive subject matter, the datatransfer interface may be electronically coupled to a person other thanthe user of the analytical device to provide data from the detector,multi-reagent pack, automatic pipette, sample processing platform, orother component (hard drive, CPU, pipette rack, etc.). Suchconfigurations may be especially advantageous where an analytical devicehas become inoperable or provide a user with an error notification. Theuser may then activate electronic communication (manually or by default)between the data transfer interface and a computer in a remote location,wherein a person other than the user (e.g., service technician) requestor receives the status data to provide immediate diagnosis of theanalytical device from a remote location. The term “person other thanthe user” as used herein refers to a person does not initiate, continue,or terminate (including analysis of test results) a test using theanalytical device, typically while proximal to the analytical device.The term “proximal to the analytical device” as used herein means withinthe same room, or associated with the data generated by the analyticaldevice (e.g., a physicians office). Thus especially contemplated personsother than a user include sales staff for components or reagents of theanalytical device, service technicians of the analytical device, etc.

With respect to the step of providing the data, it should be recognizedthat all known methods of data transfer are contemplated, particularlyincluding the person other than the user remotely requesting data, andthe user initiating electronic communication between the analyticaldevice and the person other than the user. Thus, the step of providingmay preferably be executed via an Internet or via a modem connection andmay be performed in response to an action of the user of the analyticaldevice.

Particularly contemplated data include type of reagent in themulti-reagent pack, volume of at least one reagent in the multi-reagentpack, volume of liquid transferred using the automatic pipette,temperature of the sample processing platform, type of test performedusing the analytical device, batch number of reagent in themulti-reagent pack, date manufactured of reagent in the multi-reagentpack, and expiration date of reagent in the multi-reagent pack.Consequently, the operational status will include inoperability (e.g.,inoperable due to lack of reagent, inoperable due to failure of theautomatic pipette, inoperable due to incompatibility of reagent with aselected test, and/or inoperable due to failure of the detector) of theanalytical device, current activity of the analytical device (e.g.,pipetting, focusing, detecting, etc.), and supply status (e.g., how manytest reagents left).

Therefore, a further particularly contemplated aspect of the inventivesubject matter includes a method of marketing in which an analyticaldevice is provided, wherein the device comprises a data transferinterface that receives status data of a component in the analyticaldevice. The data transfer device is then electronically coupled to asystem in a remote location relative to the analytical device, and thedata transfer device provides then the status data to the remote systemusing the data transfer interface, wherein the status data are used inthe remote system (or analytical device) to initiate delivery of areplacement for the component.

With respect to the analytical device, the data transfer interface,status data, the component, the same considerations as discussed aboveapply. Particularly preferred analytical devices include those thatanalyze binding of an analyte to a substrate on a biochip. However,numerous other analytical devices are also considered suitable andinclude analytical and/or preparative systems (e.g., HPLC, GC, etc.).Further especially preferred components include reagents (solid, liquid,or gaseous), wherein the status data of the component is (remaining)volume of the reagent in the analytical device. However, non-reagentcomponents, and especially disposable non-reagent components are alsocontemplated. Thus suitable components include pipette tips, wherein thestatus data of the component is the number of remaining pipette tips inthe analytical device

It should further be recognized that the step of electronically couplingmay include a permanent coupling or a temporary coupling (e.g., user, ordevice initiated). However, especially suitable couplings includecoupling the analytical device with an Internet. In further contemplatedaspects, the step of providing the status data is controlled by apredetermined schedule executed on a processor of the analytical device.Alternatively, the step of providing the status data may be controlledby a predetermined schedule executed on a processor of the system in theremote location.

It is generally contemplated that the status data may be used in theremote system (or in the analytical device) to initiate delivery of areplacement for the component. The term “initiate delivery” as usedherein refer to an event leading to a decision whether or not to providea customer with a product. Thus, initiation of delivery may includeautomatic generation of a purchase order, automated offer to purchasefrom the remote system to the analytical device, etc. Consequently,contemplated methods and configurations may be employed for inventorycontrol and management on the side of the operator of the analyticaldevice.

Therefore, contemplated systems will provide an operator with thecapability to quantitatively and qualitatively analyze one or moreanalytes in one or more samplea with minimum manual intervention. Forexample, while numerous known systems separate sample and/or analytehandling (e.g., application, washing, hybridization) from analytedetection, the contemplated system will in one preferred aspect performsample and/or analyte handling and analyte detection in an automated andtypically continuous manner.

Thus, contemplated systems will include the following subsections:Sample and reagent handling, disposable handling, microarray processing,stringency station, optical detection system, waste handling, anddata/result analysis. These sections handle all the processing requiredfor DNA and Proteomic analysis for the following not exclusive list: SNPand STR analysis, microsatellite analysis, gene- and protein expressionanalysis, and protein quantification and identification.

Consequently, one or more of the following processing steps may beincluded in contemplated analytic systems: Sample and reagent dispensingoperations, analysis of environmental conditions for sample and reagent,wash processes using aspiration dispenser, ultrasonic energy and heat,use of ultrasonic energy for mixing to improve hybridization andbinding, bar code for reagent tracking and sample identification, sonicirradiation for chip surface detection, laser irradiation for volume andsurface detection, and the use of a reagent module as a communicationlink between at least two of manufacturing, assay development scientist,user and technical support without any intervention from the operator.In further contemplated aspects, stringency is preferably controlled atleast in part determined by heat (e.g., thermal stringency for improvingspecificity), and optical detection employs a two wavelength system forexcitation and detection using confocal microscope technology. Assaydevelopment software is contemplated to assist in automation of newtests.

In yet further contemplated aspects, the software/operator interfacewill provide the system with specific test requirement for a specificsample, which may be downloaded from a host computer. Furthermore, it iscontemplated that the interface may also be used to transmit resultsthrough web or modem. Thus, a contemplated operation communication linkmay include an integrated color monitor, a mouse and keyboard, a R/W CD,40 GB of hard drive, and bioinformatics software for data/resultanalysis.

Thus, specific embodiments and applications of integrated micro arraysystems have been disclosed. It should be apparent, however, to thoseskilled in the art that many more modifications besides those alreadydescribed are possible without departing from the inventive conceptsherein. The inventive subject matter, therefore, is not to be restrictedexcept in the spirit of the appended claims. Moreover, in interpretingboth the specification and the claims, all terms should be interpretedin the broadest possible manner consistent with the context. Inparticular, the terms “comprises” and “comprising” should be interpretedas referring to elements, components, or steps in a non-exclusivemanner, indicating that the referenced elements, components, or stepsmay be present, or utilized, or combined with other elements,components, or steps that are not expressly referenced.

1. A method of analyzing an analyte on a biochip, comprising: providingan analytical device comprising a first section and a second sectionthat receive a biochip having a plurality of substrates in a pluralityof predetermined positions; contacting the biochip in the first sectionwith a sample containing a non-analyte and an analyte under conditionsthat allow binding of the analyte to at least one of the substrates;operationally coupling the first section to the second section such thatthe biochip is automatically transferred from the first section to thesecond section; optically detecting with an optical device in the secondsection binding of the analyte to the at least one of the substrates onthe biochip, wherein a focal plane of the optical device is determinedusing a reference signal from a reference marker that is disposed on thebiochip; and wherein the reference marker is illuminated by a firstlight source at a first angle, and wherein at least one of the pluralityof substrates is illuminated by a second light source at a second angle,and wherein the housing is configured such that the first angle and thesecond angle are not identical.
 2. The method of claim 1 wherein thebiochip is provided to the first section from a magazine using anautomatic actuator, wherein the magazine is disposed within theanalytical device.
 3. The method of claim 1 wherein the first section isconfigured to receive at least a second biochip.
 4. The method of claim1 wherein the first section further comprises an energy source.
 5. Themethod of claim 4 wherein the energy source is selected from the groupconsisting of an ultrasound source, a microwave source, a heater, and acooler. the analyte is selected from the group consisting of a tissue, anucleic acid, a peptide, and an enzyme inhibitor.
 7. The method of claim1 wherein the plurality of substrates comprise at least one of a nucleicacid, a peptide, and an enzyme inhibitor, and wherein at least one ofthe plurality of substrates is non-covalently coupled to the biochip viaa crosslinker.
 8. The method of claim 1 wherein the step of contactingincludes pipetting the sample with an automatic pipette that is disposedwithin the analytical device.
 9. The method of claim 1 wherein the stepof contacting includes heating the biochip within the analytical device.10. The method of claim 1 wherein the step of operationally couplingincludes providing an automatic actuator that moves the biochip from afirst platform of the first section to a second platform of a secondsection.
 11. The method of claim 1 wherein the step of opticallydetecting includes a confocal microscope or a dark field microscope. 12.(canceled)
 13. The method of claim 1 wherein the step of opticallydetecting comprises detecting a signal selected from the groupconsisting of a fluorescence signal, a chemiluminescence signal, and aphosphorescence signal.
 14. The method of claim 1 further comprising:providing a second biochip having a plurality of second substrates in aplurality of predetermined positions; contacting the second biochip inthe first section with a sample containing a second non-analyte and asecond analyte under conditions that allow binding of the second analyteto at least one of the second substrates of the second biochip; whereinthe plurality of substrates comprises a nucleic acid, and wherein theplurality of second substrates comprises a peptide. providing a biochiphaving a housing with a reference marker and a plurality of substrates,wherein at least one of the substrates binds an analyte; illuminatingthe reference marker to create a reference signal, and illuminating theanalyte to create an analyte signal; determining a focal plane for anoptical detector using the reference signal and adjusting the opticaldetector to the focal plane; wherein the reference marker is illuminatedby a first light source at a first angle, and wherein at least one ofthe plurality of substrates is illuminated by a second light source at asecond angle, and wherein the housing is configured such that the firstangle and the second angle are not identical; and acquiring the analytesignal using the optical detector.
 16. The method of claim 15 whereinthe reference marker comprises a compound selected from the groupconsisting of a fluorophor, a luminogenic substrate, or a phosphorescentcompound.
 17. The method of claim 15 wherein the at least one of thesubstrates is selected from the group consisting of a nucleic acid, apeptide, and an enzyme inhibitor, and wherein the at least one of thesubstrates is non-covalently coupled to the biochip via a crosslinker.18. The method of claim 15 wherein the binding of the analyte to the atleast one of the substrates is non-covalent binding.
 19. The method ofclaim 15 wherein the step of providing the biochip comprises moving thebiochip from a sample processing platform to a detector using anautomatic actuator.
 20. The method of claim 15 wherein the step ofilluminating the reference marker comprises illumination of thereference marker in a dark field.
 21. The method of claim 15 wherein thestep of illuminating the analyte comprises illumination with a laser.22. The method of claim 15 wherein illuminating the reference marker andilluminating the analyte are performed using independent light sources.23. The method of claim 15 wherein the optical detector comprises aconfocal microscope.
 24. The method of claim 15 wherein the analytesignal is a signal selected from the group consisting of a fluorescencesignal, a chemiluminescence signal, and a phosphorescence signal.
 25. Amethod of operating an analytical device, comprising: providing ananalytical device comprising a data transfer interface coupled to atleast one of a detector, a multi-reagent pack, an automatic pipette, anda sample processing platform; electronically coupling the data transferinterface with a person other than a user of the analytical device;providing data to the person other than the user from at least one ofthe detector, the multi-reagent pack, the automatic pipette, and thesample processing platform to the person via the data transferinterface; and using the data to analyze operational status of theanalytical device.
 26. The method of claim 25 wherein the person otherthan the user is in a remote location relative to the analytical device.27. The method of claim 25 wherein the step of providing is executed viaan Internet or via a modem connection.
 28. The method of claim 25wherein the step of providing is performed in response to an action ofthe user of the analytical device.
 29. The method of claim 25 whereinthe data is selected from the group consisting of type of reagent in themulti-reagent pack, volume of at least one reagent in the multi- thesample processing platform, type of test performed using the analyticaldevice, batch number of reagent in the multi-reagent pack, datemanufactured of reagent in the multi-reagent pack, and expiration dateof reagent in the multi-reagent pack.
 30. The method of claim 25 whereinthe operational status is selected from the group consisting ofinoperable due to lack of reagent, inoperable due to failure of theautomatic pipette, inoperable due to incompatibility of reagent with aselected test, and inoperable due to failure of the detector.
 31. Amethod of marketing comprising: providing an analytical devicecomprising a data transfer interface that receives status data-of acomponent in the analytical device, and wherein the analytical devicedetermines the status data; electronically coupling the data transferinterface with a system in a remote location relative to the analyticaldevice; providing the status data to the remote system using the datatransfer interface; and using the status data in the remote system toinitiate delivery of a replacement for the component.
 32. The method ofclaim 31 wherein the analytical device analyzes binding of an analyte toa substrate on a biochip.
 33. The method of claim 31 wherein thecomponent is a reagent and wherein the status data of the component isvolume of the reagent in the analytical device.
 34. The method of claim31 wherein the component is a pipette tip and wherein the status data ofthe component is number of remaining pipette tips in the analyticaldevice.
 35. The method of claim 31 wherein the step of electronicallycoupling includes coupling the analytical device with an Internet. 36.The method of claim 31 wherein the step of providing the status data iscontrolled by a predetermined schedule executed on a processor of theanalytical device. a predetermined schedule executed on a processor ofthe system in the remote location.
 38. The method of claim 31 whereininitiation of delivery includes automatic generation of a purchaseorder.